CD55 regulates self-renewal and cisplatin resistance in endometrioid tumors.

Autor:	Saygin C; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH., Wiechert A; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.; Department of Obstetrics and Gynecology, Women's Health Institute, Cleveland Clinic, Cleveland, OH., Rao VS; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH., Alluri R; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH., Connor E; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.; Department of Obstetrics and Gynecology, Women's Health Institute, Cleveland Clinic, Cleveland, OH., Thiagarajan PS; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH., Hale JS; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH., Li Y; Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH., Chumakova A; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH., Jarrar A; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH., Parker Y; Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH., Lindner DJ; Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH., Nagaraj AB; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH., Kim JJ; Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL., DiFeo A; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH., Abdul-Karim FW; Pathology and Laboratory Medicine Institute, Department of Anatomical Pathology, Cleveland Clinic, Cleveland, OH., Michener C; Department of Obstetrics and Gynecology, Women's Health Institute, Cleveland Clinic, Cleveland, OH., Rose PG; Department of Obstetrics and Gynecology, Women's Health Institute, Cleveland Clinic, Cleveland, OH., DeBernardo R; Department of Obstetrics and Gynecology, Women's Health Institute, Cleveland Clinic, Cleveland, OH., Mahdi H; Department of Obstetrics and Gynecology, Women's Health Institute, Cleveland Clinic, Cleveland, OH., McCrae KR; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH., Lin F; Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH., Lathia JD; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH lathiaj@ccf.org.; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH.; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH., Reizes O; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH reizeso@ccf.org.; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH.; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2017 Sep 04; Vol. 214 (9), pp. 2715-2732. Date of Electronic Publication: 2017 Aug 24.
DOI:	10.1084/jem.20170438
Abstrakt:	Effective targeting of cancer stem cells (CSCs) requires neutralization of self-renewal and chemoresistance, but these phenotypes are often regulated by distinct molecular mechanisms. Here we report the ability to target both of these phenotypes via CD55, an intrinsic cell surface complement inhibitor, which was identified in a comparative analysis between CSCs and non-CSCs in endometrioid cancer models. In this context, CD55 functions in a complement-independent manner and required lipid raft localization for CSC maintenance and cisplatin resistance. CD55 regulated self-renewal and core pluripotency genes via ROR2/JNK signaling and in parallel cisplatin resistance via lymphocyte-specific protein tyrosine kinase (LCK) signaling, which induced DNA repair genes. Targeting LCK signaling via saracatinib, an inhibitor currently undergoing clinical evaluation, sensitized chemoresistant cells to cisplatin. Collectively, our findings identify CD55 as a unique signaling node that drives self-renewal and therapeutic resistance through a bifurcating signaling axis and provides an opportunity to target both signaling pathways in endometrioid tumors. (© 2017 Saygin et al.)
Databáze:	MEDLINE
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